The Aging Brain Matrix: Cross-Species Evidence Linking FREM3 to Brain and Cognitive Aging
- 1Centre for Addiction and Mental Health
Abstract
The human extracellular-matrix-related FREM3 gene is strongly age-dependent, enriched in age-sensitive excitatory long-range-projecting neurons, and implicated in neurodegenerative diseases. To establish the first translationally relevant causal evidence for the role of FREM3 in brain structure and cognition, we developed an excitatory-neuron-specific Frem3 conditional knockout mouse model (Frem3-cKO) and computed genetically regulated expression of FREM3 (FREM3-GReX) in humans, enabling convergent neurostructural and cognitive characterizations. Frem3-cKO mice showed widespread lower global and regional brain volume in middle age vs young adulthood, consistent with drastic age-dependent volume loss absent in wildtype mice. These effects were strongest in cognitively relevant cortical regions and paralleled by lower cognitive performance. In humans, lower FREM3-GReX was associated with lower total surface area, which further mediated an indirect link to lower cognitive performance across multiple age-sensitive domains. We provide the first translationally relevant cross-species evidence supporting a key role for FREM3/Frem3 in maintaining brain and cognitive health across aging.
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BibTeX
@misc{clifford2026aging,
title = {{The Aging Brain Matrix: Cross-Species Evidence Linking FREM3 to Brain and Cognitive Aging}},
author = {K. P. Clifford and T. D. Prevot and A. Sumitomo and Y. Bansal and S. Das and M. Marcotte and R. Zhou and J. Yeung and M. Ding and D. Felsky and B. Nieman and M. Banasr and E. Sibille and T. Tomoda and Y. Nikolova},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762265},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762265v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The Aging Brain Matrix: Cross-Species Evidence Linking FREM3 to Brain and Cognitive Aging
AU - K. P. Clifford
AU - T. D. Prevot
AU - A. Sumitomo
AU - Y. Bansal
AU - S. Das
AU - M. Marcotte
AU - R. Zhou
AU - J. Yeung
AU - M. Ding
AU - D. Felsky
AU - B. Nieman
AU - M. Banasr
AU - E. Sibille
AU - T. Tomoda
AU - Y. Nikolova
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762265
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762265v1
AB - The human extracellular-matrix-related FREM3 gene is strongly age-dependent, enriched in age-sensitive excitatory long-range-projecting neurons, and implicated in neurodegenerative diseases. To establish the first translationally relevant causal evidence for the role of FREM3 in brain structure and cognition, we developed an excitatory-neuron-specific Frem3 conditional knockout mouse model (Frem3-cKO) and computed genetically regulated expression of FREM3 (FREM3-GReX) in humans, enabling convergent neurostructural and cognitive characterizations. Frem3-cKO mice showed widespread lower global and regional brain volume in middle age vs young adulthood, consistent with drastic age-dependent volume loss absent in wildtype mice. These effects were strongest in cognitively relevant cortical regions and paralleled by lower cognitive performance. In humans, lower FREM3-GReX was associated with lower total surface area, which further mediated an indirect link to lower cognitive performance across multiple age-sensitive domains. We provide the first translationally relevant cross-species evidence supporting a key role for FREM3/Frem3 in maintaining brain and cognitive health across aging.
ER -